1 D R A F T WHITE PAPER 2 3 Regulators Work Toward Harmonizing Safe Medication Container Labeling and 4 Packaging 5 6 INTRODUCTION 7 8 The complexity of the medication management system continually introduces factors that can 9 compromise its safety and that of patients at large. 1 Globally, it is estimated that 64 million disability- 10 adjusted life years are lost yearly due to unsafe care. 2 The presentation of the primary and secondary 11 packaging of drugs is a determining factor in how they are identified and used.3 Aspects such as unclear, 12 ambiguous medicine label information and similarities in appearance can lead to selection errors and 13 inappropriate use including wrong drug, formulation, dose, or route of administration errors. 4,5,6 With 14 the world becoming a global village, addressing the differences in global product labeling and packaging 15 becomes vitally important. A study of international generic drugs highlighted the non-equivalence in the 16 labeling and packaging standards for these products. 7 Such differences create potential for medication 17 errors to occur. In 1998, more than one third (33%) of medication errors reported to United States 18 Pharmacopeia’s (USP) voluntary error reporting program involved product labeling or packaging. 8 In 19 2001, Kenagy and Stein 9 estimated that medication errors related to labeling and packaging injure or kill 20 about 10,000 patients yearly. 21 Medication errors affect millions of patients around the world, sometimes leading to death or serious 22 harm. Globally, the cost associated with medication errors has been estimated at $42 billion USD 23 annually 10 . Each year in the U.S., serious preventable medication errors occur in 3.8 million inpatient 24 admissions and 3.3 million outpatient visits.11,12 Recently, the National Health Services (NHS) in England 25 estimated that 237 million of medication errors occur at some point in the medication use process per 26 year.13 A landmark study published in 2000 estimated that as many as 98,000 people die each year in 27 the US from medical errors occurring in hospitals. Medication errors is a significant public health 28 concern that accounts for an estimated 7,000 deaths annually in the US 14 and contributes to 1,708 29 deaths in England. 13 30 In 2011, the Network for Excellence in Health Innovation reported that outpatient and inpatient 31 preventable medication errors cost approximately $20 billion each year.15 The NHS in England places 32 the estimated cost of avoidable adverse drug reactions at £98.5 million per year, consuming 181,626 33 bed-days.13 A recent study in the European Union (EU) showed a steady increase in the number and 34 proportion of Individual Case Safety Reports (ICSRs) of medication errors in the EudraVigilance database 35 between 2002 and 2015, to a peak of 5% of all ICSRs in the database. 16 36 37 Though the true incidence is unknown, preventable medication errors significantly increase healthcare 38 cost. Problems associated with medications are common.17 While multiple interventions addressing the 39 frequency and impact of medication errors have been developed, their implementation varies.17 To 40 achieve a reduction of overall harm related to medication errors, harmonization at the global level is 41 necessary. Many of the product labeling, packaging and naming issues are common across the 42 countries. 43 44 BACKGROUND

45 An analysis of medication errors related to labeling and packaging indicated that look-alike labeling and 46 packaging; use of dangerous or misleading abbreviations; lack of clarity with expression of strength; lack

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47 of prominence of non-proprietary name (generic name); legibility and readability of information; 48 contributed to medication errors.18 A lack of consistent drug container labeling and packaging across the 49 globe can contribute to errors especially because some countries rely solely on imported drugs, others 50 also import drugs to address drug shortages in their country. To advance global harmonization of 51 container labeling and packaging standards and reduce overall harm associated with medication errors, 52 the International Medication Safety Network (IMSN) and the US Food and Drug Administration (FDA) 53 held a summit for regulators on drug container labeling and packaging safety in June 2018 54 (https://www.intmedsafe.net/global-regulators-and-safety-advocates-meet-about-drug-container- 55 labelling-and-packaging/ ). Goals of the summit included the creation of a minimum set of best practices 56 for pharmaceutical container labeling and packaging aimed at reducing medication errors and the 57 implementation of support for safety technologies such as label barcodes to be used with scanning 58 equipment to reduce medication errors. 59 60 The summit was held at the FDA White Oak (Silver Spring) campus in MD, and convened a group of 61 regulators, FDA staff, IMSN members, and invited international speakers. The meeting was co-chaired by 62 FDA’s Lubna Merchant, Deputy Director of the Office of Medication Error Prevention and Risk 63 Management and Acting Director of the Division of Medication Error Prevention and Analysis, and 64 Michael Cohen, chair of IMSN and president of the Institute for Safe Medication Practices (ISMP). 65 66 Summit participants included the Brazilian Health Regulatory Agency (ANVISA), Mexico Federal 67 Commission for the Protection against Sanitary Risks (COFEPRIS), European Medicines Agency (EMA), 68 Health Canada, Portugal National Authority of Medicines and Health Products (INFARMED), Netherlands 69 Medicines Evaluation Board (MEB), United Kingdom Medicines & Healthcare products Regulatory 70 Agency (MHRA), Saudi Food and Drug Authority (SFDA), FDA, WHO, IMSN members (ISMP, ISMP Canada, 71 ISMP Spain, United Arab Emirates, Danish Patient Safety Authority, and Canadian Patient Safety 72 Institute) and Global Standards One (GS1). 73 74 Recognizing the importance of pharmaceutical industry’ involvement when addressing safer drug 75 container labeling and packaging, the proceedings from the June 2018 meeting were discussed during a 76 follow-up meeting (as part of IMSN 13 th Annual meeting) held in October 2018 (Cascais, Portugal). 77 Participants included, representatives of pharmaceutical companies (Abbvie, USA; Baxter, Portugal; 78 BMS, USA; Eli Lilly, UK; Hikma, USA; Janssen/J&J, Netherlands; Novartis, USA; Pfizer, USA; UCB, USA), 79 medicine agencies (FDA, USA; ANVISA, Brazil; MHRA,UK; Norway Medicine Agency), WHO (via 80 teleconference), IMSN members (ISMP, ISMP Canada, ISMP Spain, ISMP Brasil, Prescrire, Hong Kong 81 health authority, Portuguese Association of Hospital Pharmacists (APFH), United Arab Emirates, and 82 Health Quality and Safety Commission New Zealand [HQSC]). Also, in attendance were 83 pharmacovigilance centers: Centre anti poison et de pharmacovigilance du Maroc, FDA, French network 84 of regional pharmacovigilance, MHRA, New Zealand Pharmacovigilance Center, Norway Medicine 85 Agency, Portuguese Pharmacovigilance, and Drug Commission of the German Medical Association), and 86 others (Organizacion de Farmaceuticos Ibero Latinoamericanos, Brand Institute, and Med-ERRs). 87 88 Meeting participants strongly advocate for the global acceptance of ten drug container labeling and 89 packaging recommendations brought forth in this document. These recommendations are intended for 90 container labels and carton labeling for drug and therapeutic biological products, although they may 91 also be relevant for other products. While many safe drug container labeling and packaging practices 92 were discussed, the purpose of this paper is to limit the discussion of the recommendations that the 93 summit participants agreed upon. 94

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95 96 97 98 RECOMMENDATIONS 99 100 Immediate and outer container labels 101 102 1. For small volume injectable products, the product strength should include the amount per mL 103 and the total quantity per volume. 104 105 A product’s strength or concentration is critically important information. Healthcare professionals 106 rely on the amount of ingredient (strength) in a drug to properly treat patients.19 Strength 107 expression is an essential piece of information on product labels, unclear expression of strength 108 can lead to incorrect selection and use of products.20 Volume mismatch of product in the 109 container with the expression of strength (i.e., the strength expression on the label states the 110 amount of product per milliliter, but the vial contains more than 1 mL) has introduced confusion 111 leading to medication errors.21 Such errors have been reported for decades. For example, a nurse 112 and medical resident inadvertently administered 30,000 units of heparin instead of 3,000 units. 113 Both practitioners thought a 10 mL vial of heparin held a total of 1,000 units when, in fact, each 114 vial contained 10,000 units (1,000 units/mL). This mistake led to the death of the patient after 115 development of an intracranial hemorrhage and brain stem herniation.21 116 117 Many regulators already demand for products to be labeled with both the per mL and the per 118 container quantity.3,20,22,23,24,25 While EMA and MHRA require the per container quantity to be 119 prominently displayed on the label, the FDA and Health Canada explicitly recommend the product 120 strength to be expressed as total quantity per total volume followed in close proximity by the 121 concentration per mL in parenthesis. There may be some exceptions (noted below) to expressing 122 strength per total volume. In certain cases, the primary and prominent expression of the total 123 drug content per container would not be effective in preventing medication errors, for example; 124 125 - Containers with less than 1 mL total volume, only the amount per volume provided (e.g., 3 mg 126 / 0.5 mL) should be listed. 20,25 127 - Unit dose ready-to-use formats such as prefilled syringes, only the amount per volume 128 provided should be listed (e.g., 6 mg / 1.2 mL, 4 mg / 0.8 mL). The per ml amount can be 129 provided in the prescribing information. 20 130 131 This position is also supported by IMSN 4, Pharmaceutical Management Agency (PHARMAC) 26 , and 132 United States Pharmacopoeia (USP) 27 . Prominently labeling products with both the total quantity 133 per total volume and amount per mL can help avoid confusion and reduce the risk of medication 134 errors. 135 136 137 2. Use of metric units in the strength expression for products. 138 139 The strength expression on product labels should appear in metric units of measure such as mL, 140 mg, mcg or g, rather than non-metric units. Apothecary or household measurements such as 141 teaspoon, drams, grains or ratios (e.g., 1:1000) should not be used. There is a need for healthcare 142 practitioners to understand how to measure the correct dose of a medication. Unit conversion

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143 errors are common. Fatal medication errors have occurred when healthcare providers or patients 144 are converting from one unit of measure to another.25 Conversion and calculating errors can be 145 prevented via the use of a standard unit thereby reducing the need for conversion. 28 Wheeler et 146 al 29 reported an increased number of errors when the concentration of EPINEPH rine was 147 expressed as a ratio (1:1,000) compared with metric units (1 mg/ml). 148 149 Many error cases have been published related to the ratio expression of medication strength 150 including the death of a teenage boy being treated for priapism. The physician misunderstood the 151 ratio expression of EPINEPH rine 1:1,000 and inadvertently administered 4 mL of undiluted 152 EPINEPH rine 1:1,000 (4 mg) instead of 4 mL of 1:1,000,000 (a dose normally prepared by diluting 1 153 mg of EPINEPH rine 1:1,000 in a liter of normal saline).30 154 155 In an effort to improve patient safety, on May 1, 2016, USP eliminated ratio expression for single 156 entity drug labels such as EPINEPH rine, neostigmine, and isoprotenol. 31 157 Drug regulators recognize that a product's strength or concentration is critically important 158 information for the end user. Since the purpose of expressing strength in the name of a product is 159 to give the most relevant information regarding the content of the product in view of its use 23 , it is 160 therefore important to express the dose strength of health products in appropriate metric unit 161 system.20 To allow for safe transition to metric-only labelling, the strength on container labels 162 should be expressed in both metric unit as well as the formal unit in parenthesis during the 163 transition period.32 The use of metric units to express the dose of drug products have been 164 supported by IMSN, 4 FDA, 25 Health Canada, 20 Australian Therapeutic Goods (TGA), 33 FIP 34 , and 165 others. 166 167 Although, there was consensus on the use of metric units, it is important to note that there may 168 be a few exceptions to the use of metric units for strength expression. For example, units of 169 measure other than metric may be acceptable in certain situations, such as expressing the 170 potency for certain biological products or percentage strength for topical preparations. It is 171 important to consider older expressions of strength for which there has been a historical practice 172 and understanding among users without evidence of medications errors. Changes to expressions 173 of strength in these few cases may be problematic if the strength has been expressed in a non- 174 metric unit without evidence of medication errors. 175 176 Also, strengths and concentrations should consistently be expressed in units of measure that are 177 congruent with those used in the dosing instructions.20,25 178 179 3. Eliminate potentially error-prone abbreviations and dose designations on immediate and outer 180 container labels. 181 182 Communication failures in healthcare contribute to errors. In fact, this accounted for more than 183 20% of sentinel events in 2014.35 Certain abbreviations used to communicate medication orders 184 can lead to communication lapses. 36 Concerns about error-prone abbreviations and dose 185 designations led The Joint Commission (TJC) to introduce the “Do Not Use” list of abbreviations as 186 part of its National Patient Safety Goals in 2004. 37 In addition to TJC, ISMP, ISMP Canada, the 187 National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP), 188 Accreditation Canada, and the Health Quality of Alberta advocate for the prohibition of dangerous 189 abbreviations and dose designations. 38 190

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191 Despite this advocacy, several instances of medication errors related to the use of abbreviations 192 have been reported. In a study to determine patient harm related to the use of abbreviations, the 193 use of “U” for units accounted for 13.1% of errors.36 The use of the abbreviation “U” contributes 194 to errors when misread as zero (0), often leading to 10-fold or greater overdose. 39,40 Such errors 195 can be particularly dangerous when insulin units are involved, but other drugs are also measured 196 in units and just as prone to serious overdose errors. Another abbreviation of units that has been 197 reported is the use of “IU” for international units, which has been mistaken as intravenous 198 (IV) 36,40,41,42 For example, in preparing a dose of “Vitamin E 100 IU,” a nurse misinterpreted “IU” as 199 “IV” and drew up the content of the oil-based capsule into a syringe for IV administration. 200 Fortunately, the mistake was noticed before administration to the patient.43 201 202 The use of trailing zeros (e.g., 1.0) is another concerning dose designation. In a study that 203 evaluated the use of dangerous abbreviations and dose designations, errors related to trailing 204 zeros increased between January 2005 and 2009. 38 If decimal places or commas are not seen, it 205 can lead to a 10-fold overdose or underdose.20 206 207 The use of naked decimal points (e.g., .5) should also be avoided. Fatal errors have been published 208 regarding naked decimal points, such as the tragic death of a 9-month-old baby who received 10 209 mg of IV morphine within two hours. The physician had prescribed “.5 mg” of IV morphine but the 210 order was inadvertently transcribed as 5 mg of IV morphine. 44 211 212 To improve the safety of drug labels globally, it is crucial to avoid error prone abbreviations and 213 dose designations. Many regulators and organizations already recommend against the use of 214 trailing zeros, “U” for units e.g., Health Canada,20 FDA,25 Australian commission on Safety and 215 Quality in Heathcare,41 FIP, 34 HQSC,41 and “IU” for international units on drug labels e.g., Health 216 Products Regulatory Authority,22 PHARMAC 26 Australian commission on Safety and Quality in 217 Healthcare.41 218 219 There may be instances where it is not be feasible to avoid use of these abbreviations especially 220 for multilingual labels given the limited space on labels. However, whenever feasible, these 221 abbreviations should be avoided. 222 223 4. Prominently display cautionary statements on outer and immediate container labels of 224 neuromuscular blockers, potassium chloride concentrate injection, methotrexate, and other 225 selected error-prone medications. 226 227 Some medications have an increased risk of causing significant patient harm (especially when used 228 inappropriately), which should be highlighted on the label. Fatal errors with high-alert 229 medications, such as neuromuscular blockers (e.g., suxamethonium [succinylcholine], rocuronium, 230 vecuronium), methotrexate, and potassium chloride concentrate injection have been averted due 231 to a prominent display of cautionary statements. For example, a nurse inadvertently selected 232 succinylcholine instead of heparin. While walking to the patient’s bedside, she noticed white 233 lettering on the red cap that read “WARNING: PARALYZING AGENT”, which prompted her to verify 234 the vial thereby preventing a medication error. She indicated that the prominently displayed 235 cautionary statement enabled her to identify this near miss. 45 When first noticed, even when the 236 product is not in active use, such as when seen while in storage, these brief warning statements 237 also serve to educate users about medication properties of which they may not be aware. 238

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239 Designing warnings is a complicated task that should be based on human factors and practice 240 considerations. 46 Warning or cautionary statements convey critical information about the product 241 to the user, to facilitate correct product use and to prevent an error that may result in serious 242 harm or death. 47 243 244 Since evidence has demonstrated that the effectiveness of warnings and messages increases with 245 prominence 48 , the guidance documents of some countries and organizations state that these 246 warning should be the most prominent information on the label and package 25,26 ; be positive and 247 affirmative 4,20,24,25 ; brief and explicit 20,47 ; and incorporate signal words (e.g., “DANGER” 248 "WARNING", "ALERT").20 249 250 Examples of warnings approved by some regulators and organizations include: Vinca alkaloids “For Intravenous Use Only – Fatal If Given by Other Routes”(IMSN,4 Health Canada, 20 USP, 47 MHRA 49 ) Oral methotrexate “Check dose and frequency – Methotrexate is usually taken once a week” (IMSN,4 Health Canada, 20 MHRA 49 ) Potassium Chloride concentrate injection “Mus t Dilute Before Use” (IMSN ,4 Health Canada, 20 MHRA 49 ) Neuromuscular blocking agents “Warning : Paralyzing Agent” (Health Canada, 20 ISMP Canada,45 TGA 50 ) 251 252 Some regulators allow for cautionary statements to be included in the product labeling or on the 253 surface of the ferrule or cap overseal of a vial containing an injectable product. 20,25 To globally 254 prevent medication errors related to these vinca alkaloids, oral methotrexate, potassium chloride 255 concentration injection, and neuromuscular blocking agents, cautionary statements/special 256 warnings should be prominently applied to the product label. 257 258 Also, these cautionary statements should have a consistent message globally e.g., the message on 259 the warning label for neuromuscular blocking agents in Europe should be the same for 260 neuromuscular blocking agents in Australia, USA, Canada etc. 261 262 5. For the labels on glass ampules, contrasting label backgrounds and appropriate font size and 263 label orientation should be used, to improve readability. 264 265 Glass ampules have been widely used in packaging injectable drugs especially in emerging 266 markets 51 due to the low cost of production.52 However, poor glass ampule labeling continually 267 contributes to medication errors. Ampules with a clear background have a poor contrast and are 268 difficult to read, especially when the printing is black or another dark color.53 Overlapping text 269 printed on both sides of an ampule and poor visual contrast between container closure and label 270 information; text and background, has led to wrong drug and dose errors. 25 Abeysekara et al 54 271 stated that 20.8% of drug errors reported to the Australian incident monitoring program were due 272 to wrong drug ampule selection or a labeling error. Studies have demonstrated that using a 273 contrasting background on ampule labels improves legibility and decreases reading errors.55,56 274 275 Besides contrasting background, font size and label orientation also affect the legibility of ampule 276 labels. In 2004, ASTM International published guidelines on the labeling of ampules which were

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277 accepted by the American Society of Anesthesiologist (ASA).57 The ASTM International guidelines 278 indicate that ampule label should have maximum contrast between the text and the background 279 provided by high contrast color combinations as specified in ASTM International standard, which 280 also minimize the impact of color blindness. 55,57 Standards also include recommendations for font 281 size, extra space for separation around the drug name, and use of additional emphasis for the 282 initial syllable, or a distinctive syllable between similar drug names. 57 These recommendations are 283 also supported by the International Organization for Standardization (ISO) and ISMP. 57,58 284 285 Also, some regulators recommend the use of color contrast that affords adequate legibility of 286 text,20,23,25 the orientation of text to the field of view so that it is not limited by physical aspects of 287 the small container (e.g., curvature), 20,26 and the avoidance of high gloss, metallic, or reflective 288 packaging.23 ISMP also recommends that ampule labeling should be oriented so that the label is 289 right side up when the neck of the ampule is held in the right hand using by thumb and forefinger, 290 thus favoring the over 80 % of human beings who are right-handed. A similar recommendation is 291 made for prefilled labeled syringes that are held in the right hand by the syringe plunger. 59 292 293 Despite reported medication errors and published standards, some manufacturers still use 294 ceramic prints on clear glass, without a contrasting background. In view of patient safety, the 295 labels on drug ampules should always have a contrasting background and appropriate readability 296 features including font size and orientation. Harmonization of ampule label requirements will 297 decrease medication errors globally. 298 299 6. Prominently display international nonproprietary names (INN) on labels/packages. 300 301 Initiated in 1950, WHO published the first list of International Nonproprietary Names (INN) for 302 pharmaceutical substances intended for use in pharmacopoeias, labeling, product information, 303 product promotional materials, drug regulations, and as the basis for product names (such as 304 generic names). 60 Most national nomenclature systems such as the British Approved Names 305 (BAN), Dénominations Communes Françaises (DCF), Japanese Adopted Names (JAN), United States 306 and TGA use names identical to INN (nonproprietary or generic drug name).60,61 307 308 The nonproprietary drug name (generic name) is a distinctive characteristic of a drug and should 309 be prominently displayed alongside other pertinent information like strength, dosage form, etc. 310 Though many countries have adopted the use of INNs, the prominence of these nonproprietary 311 drug names on drug labels varies. Not prominently displaying the generic names of medications 312 on their label may lead to medication errors including unintentional overdose.62 A Norwegian 313 study indicated that standardized and prominent placement of substance name and dose with a 314 band of high-contrast color support recognition of the active substance in medications. This 315 simple modification helps users realize that two different packages can contain the same active 316 substance, thus reducing the risk of inadvertent medication overdose. 63 317 318 For safety reasons, many organizations and regulators advocate for the prominent display of the 319 nonproprietary drug name on drug labels (e.g., MEB,3 IMSN, 4 TGA,64 European commission,65 320 Finnish Medicines Agency Administrative Regulation [FMEA],66 New Zealand medicine and Medical 321 device safety Authority [MEDSAFE]).67 Though this might be difficult for multi-component drugs, it 322 is recommended to list all active ingredients on the drug package. 22 323 324

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325 326 327 Packaging 328 329 7. Physically link or integrate “special” diluents for “specific drugs” with their powder component. 330 331 Some manufacturers package diluents commonly used for reconstitution, such as sodium chloride 332 injection 0.9% or sterile water for injection along with powdered medications as a convenience to 333 users. However, in other cases, there may be special diluents that are needed for reconstitution 334 od certain drugs and these special diluents are co-packaged with the drug product.68 When 335 medications are co-packaged with manufacturer-supplied diluents, there is risk for medication 336 errors 69 Drug products packaged with a special diluent are often separated from the diluent during 337 product storage resulting in the administration of only the diluent or incorrect reconstitution of 338 the product with the wrong diluent or an incorrect amount of diluent. 69,70 Cousins et al 71 reported 339 that wrong diluent was used in 1%, 49%, and 18% of hospital cases in the UK, Germany, and 340 France respectively. 341 342 Incorrect reconstitution may cause reduction in drug solubility, which can lead to powder 343 particulates being administered to the patient. 68,71 For vaccines, it can result in inadequate 344 protection of the patient against disease. It can also lead to product instability, precipitation 68,71 345 and contamination. Though these products usually come with information concerning the 346 diluent,68 errors related to these products are continually being reported. 347 348 Packaging these products in a container closure system that allows for the drug and diluent to be 349 physically linked or integrated will help reduce these errors. 350 351 8. Increase the adoption of ready-to-use/ready-to-administer syringes, premixed IV solutions, unit- 352 dose packaging, and other more efficient, safer packaging. 353 354 Each year, millions of prescriptions are prepared by pharmacists, nurses, and doctors.72 355 Compounded products, produced on a small scale, are necessary for patients requiring specialized 356 medication that is not commercially available. 73,74 In 2013, the US Office of the Inspector General, 357 Department of Health and Human Services, published a memorandum indicating that over 90% of 358 hospitals use compounded sterile preparations.75 However, these drugs may pose additional risks 359 to patients since regulatory oversight is less rigorous than those of commercial drugs.73,74 360 Compounded drugs are exempt from good manufacturing practice regulations, are not clinically 361 evaluated for safety or efficacy 73,74 and are not required to adhere to labeling standards,73 which 362 increases the potential for preparation errors.73,76 Sub-standard compounding practices can lead 363 to production of contaminated, super-potent, or poor-quality drugs.77 While the mention of 364 compounding errors might bring to mind the US incident in 2012 involving the New England 365 Compounding Center’s meningitis outbreak that affected hundreds of Americans,74 Flynn et al 76 366 reported a 9% error rate in the compounding of intravenous admixtures. 367 368 While compounding is an essential component of pharmacy practice, it is also common practice 369 for nurses to compound medications 78 especially in countries outside of the United States. Nurses 370 commonly prepare sterile medications for immediate or emergency use, but their focus may be on 371 the appropriateness of the drug for the patient’s diagnosis rather than pharmaceutical 372 calculations and aseptic techniques. 79 In fact, an observational study on types and frequency of

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373 errors in the preparation and administration of drugs by nurses indicated the most frequent errors 374 were lack of hand hygiene (70% in preparation phase, 81% in administration phase) and use of 375 aseptic technique (81% in preparation phase, 85% in the administration phase).80 Sterile 376 compounding by nurses in nursing units or wards; clinics; at the bedside; in procedural areas; and 377 operating rooms with little direct pharmacy oversight has an increased risk of adverse outcomes, 378 including death, that can occur if medications become contaminated or their potency is altered.78 379 Unnecessary use of compounded drugs futilely exposes patients to potentially serious health 380 risks 77 and may increase cost. In fact, fungal contamination of medications in one hospital led to 381 the readmission of 545 patients, costing the hospital system 15,000 hours of personnel time and 382 almost 900,000 US dollars.81 383 384 The purchase of ready-to-use products eliminate the need for compounding thereby reducing the 385 potential for medication errors and product contamination. 82 Ready-to-use products offer the 386 advantages of reducing preparation time, assuring the drug is properly reconstituted, lengthening 387 expiration dates, and ensuring proper labeling.83 Also, ready-to-use packages such as prefilled 388 syringes are convenient, suitable for home use, and decrease drug waste.84 With the increased 389 need to incorporate barcode scanning in the medication use process, ready-to-use products can 390 help facilitate the right product selection and administration. 391 392 Many organizations advocate for the purchase and use of premixed parenteral solutions, 393 especially for high alert medications such as concentrated electrolytes. 85 When possible, to 394 promote safe medication administration practices, regulators should encourage the use of 395 commercially prepared drugs. For products with standardized dosing, unit-dose packages should 396 be used, whenever possible. 4 Compounded products should not duplicate an approved drug 397 product.86 398 399 9. Develop product-specific global safety standards; for example, standard packaging for non- 400 oncologic methotrexate to prevent accidental daily use and overdose. 401 402 Efforts to decrease medication errors should go beyond requiring people to be infallible.87 An 403 unintentional overdose of medication might be linked to medication package design. 63 When 404 approving drug products, regulators must consider how people will use them. Consider features 405 that make products more or less safe and those that do not require humans to increase 406 vigilance. 19 407 408 Regarding the prevention of accidental daily use and overdose of methotrexate for non-oncologic 409 indications, a product feature that does not depend on human vigilance is standard packaging. 410 The dosing of methotrexate in the treatment of non-oncologic conditions, such as rheumatoid 411 arthritis, psoriasis, and other conditions, is weekly,88,89 but prescribing and dispensing errors have 412 led to patients receiving daily doses.90 A 10-year analysis by the National Patient Safety Agency in 413 the United Kingdom identified 26 cases of serious injury and 25 deaths due to unintentional 414 overdoses of methotrexate.91 415 416 Due to several reports of fatal dosing errors with methotrexate, many countries have 417 implemented safety strategies to intercept this type of error 88,89 , but the errors still exist. 418 Organizations such as IMSN 4, ISMP 90 , Prescrire 92 , and HQSC 93 propose the repackaging of 419 methotrexate in unit-dose blister calendar packs for non-oncologic indications. Since some 420 regulators indicate that the appropriate pack size should be chosen in accordance with the

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421 duration of treatment 94 , methotrexate unit-dose packages for non-oncologic indications should 422 only contain a 30-day supply. Some countries print warnings about the need for weekly dosing on 423 the primary display panel (e.g., Spain).95 424 425 10. Include barcodes on drug packaging to facilitate scanning at the bedside or other locations 426 where medications are dispensed and administered by healthcare practitioners 427 428 The quality of healthcare depends on safe medication preparation and administration. The use of 429 machine-readable coding and scanning have the potential to identify and intercept errors before 430 they reach the patient.96 Created to reduce drug administration errors and improve patient 431 safety 97 , Barcode medication administration (BCMA) has an error rate of about 1 in 10 million 432 compared to keyboard-entry error rates of 1 in 100.96,97 BCMA reduces medication errors by 433 verifying the right patient, right dose, and right drug, therefore giving a closed feedback loop. 98 434 Thompson et al 99 stated a 43.5% decrease in reported medication administration errors after the 435 introduction of BCMA and Bonkowski et al 100 noted an 80.7% relative reduction in the number of 436 administration errors after the implementation of BCMA in an emergency department. BCMA 437 systems can also be used in pharmacy stocking and retrieval to prevent dispensing errors and have 438 demonstrated financial benefits related to the cost of harmful medication errors.101 439 440 Though studies have shown that many types of errors might be avoided with the use of 441 BCMA,98,102,103 it’s use has not been adopted in many hospitals globally. A recent study indicates a 442 98.7% implementation in at least one inpatient unit but some hospitals still have not adopted its 443 use or are not using it in every unit.101 One reason BCMA has not been widely adopted at the 444 bedside globally is the lack of manufactural barcode at the unit-dose package level, requiring 445 pharmacies to manually affix organization-generated barcode labels on up to 65% of doses.96 446 447 In a separate but related issue, an increase in the global prevalence of falsified medications have 448 led to the adoption and enforcement of anti-counterfeiting laws and regulations. Over 40 449 countries have enacted track and trace laws 104 which requires drugs to have a unique product 450 identifier on each package that follows the drug throughout the distribution chain from 451 manufacturer to patient. The United States (Drug Supply Chain Security Act -DSCSA) and European 452 Union (Falsified Medicine Directive-FMD) have both enacted track and trace systems with the use 453 of the 2D (data matrix) barcode as the information carrier of the unique.3,105,106,107 The 454 incorporation of a 2D barcode for track and trace is an excellent opportunity to introduce patient 455 safety initiatives such as barcode scanning at the bedside but unfortunately, these barcodes are 456 not required on the primary drug package (unit-dose level).105,106,107 457 458 Patient safety is best achieved when practically all medications are barcoded at the primary level. 459 Since implementing barcode verification for the preparation, dispensing, and administration of 460 medications reduces the risk of errors, 108 globally, the track and trace laws should be expanded to 461 ensure that all medications sent to the point of care are barcode labeled. 462 463 464 CONCLUSION

465 In today’s society, medications play an important role and their labeling and packaging represents a vital 466 factor in their safe use.109 Medication errors related to product labeling and packaging are a global 467 patient safety issue, requiring a multi-faceted approach by international drug regulators and

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468 manufacturers. Labelling alone cannot mitigate all risk, any labeling warning or package element added 469 should be seen in the context of the overall strategy to minimize risk. Factors such as patient/caregiver 470 empowerment, healthcare professionals training and system/practice improvements employed in 471 conjunction with labelling changes to promote safer medication use.110

472 As outlined in this paper, there is a need for global harmonization of product container labeling and 473 packaging. While the content of the label and package is determined by drug manufacturers, this 474 information is assessed and approved by drug regulators. Regulatory authorities must enforce product 475 labels and packages designed to minimize medication errors. Harmonizing safer drug labeling and 476 packaging globally will decrease medication errors, decrease regulatory burden on manufacturers that 477 produce drugs for the global market, and increase the efficiency of the drug approval process. Only 478 when countries agree can we begin to advance patient safety globally.

479 REFERENCES

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Table 1: Acknowledgements and Disclosures IMSN and FDA are grateful for these volunteers and acknowledges their expertise and assistance in revising these recommendations. IMSN and FDA thank the following regulators, pharmaceutical companies, pharmacovigilance centers, and IMSN members who provided edits and comments during the review period.

Country Regulatory Agency , IMSN Members or Contact Persons Date reviewed Pharmaceutical Company USA Institute for Safe Medication Practices Michael R. Cohen January 29, (ISMP) 2019, May 17,2019 BarbraKaryne January 29, Nchinda Fobi 2019, May 17, 2019 Christina Michalek February 6, 2019 USA US Food and Drug Administration (FDA) Lubna Merchant February 22, 2019, May 17, 2019

Canada ISMP Canada David U February 26, 2019 France Prescrire Etienne Schmitt March 7, 2019

United Kingdom Medicines and Healthcare Products Jan MacDonald April 12, 2019 Regulatory Agency (MHRA) Canada Health Canada Sally Pepper May 9, 2019

European Union European Medicines Agency (EMA) Alexios Skarlatos May 16, 2019

Norway Norwegian Medicines Agency (NOMA) Sigurd Hortemo June 6, 2019

USA Bristol -Myers Squibb Yusuf Oni June 10, 2019

Alpa Bhattacharyya

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